Retinoids are promising chemopreventive agents in animals and in humans. However, because currently available retinoids are relatively toxic, retinoids are not generally used for cancer prevention. The long-term goal of our studies is to elucidate the mechanisms by which retinoids inhibit carcinogenesis in order to develop more effective and less toxic chemopreventive agents. Our preliminary studies demonstrate that 9cRA suppresses mammary tumor development in transgenic mice, but that is also induces significant toxicity. We have also shown that pathway- selective retinoids, which may be less toxic than naturally occurring broad spectrum retinoids, can inhibit the proliferation of normal and malignant breast cells. We now propose to test the hypotheses that pathway-specific retinoids will efficiently prevent breast carcinogenesis with reduced toxicity. Firstly, we will determine whether the ability of retinoids to suppress breast tumorigenesis is dependent on the specific oncogenic pathway. We will compare the chemopreventive efficacy of 9-cis retinoic acid (9cRA) in different animal models which develop breast tumors through distinct mechanisms, such as by overexpression of the c-myc or Her2/neu genes, or by chronic estrogen exposure. We will also determine whether this broad-spectrum retinoid interferes with the progression of premalignant to malignant breast tumors in these models. Secondly, we will determine which pathway-selective retinoids are able to suppress carcinogenesis in vivo. We will compare the chemopreventive efficacy and toxicity of RAR-, RXR-, and anti-AP-1-selective retinoids with that of 9cRA in animals in which 9cRA prevents breast carcinogenesis. Thirdly, we will determine whether changes in the expression of retinoid-regulated genes involved in growth regulation are associated with successful chemoprevention by retinoids. We will investigate the retinoid-induced changes in the expression of RARbeta, E-cadherin and matrix metalloproteinase-9, all of which are involved in regulating the growth and invasiveness of breast cells. We will then determine whether changes in the expression of these markers are associated with decreased proliferation, increased apoptosis, or decreased invasiveness. Through these studies we plan to identify pathway-selective retinoids which effectively prevent mammary tumorigenesis with minimal toxicity. Such investigations will provide the foundation for the development of more specific preventive retinoids and the justification for testing such agents in clinical chemoprevention trials in humans.